Alexander R. Evens, DO

Resistant gram-negative bacteria are increasingly common, and are becoming a major problem in all hospitals in the United States. Many institutions are seeing an increased prevalence of multidrug-resistant (MDR) and extensively-resistant (XDR) strains of

, a pathogen responsible for 6700 hospital-acquired MDR infections annually in the United States.

 Although polymyxins are active against most strains of MDR and XDR 

, these agents have a high toxicity and a limited therapeutic window. Consequently, there is a desperate need for new antibiotics.

The definition of MDR is a bacterium resistant to drugs from 3 separate classes of antibiotics. By definition, individuals harboring MDR organisms are high-risk patients. Many of these patients are highly antibiotic-experienced and have had multiple hospitalizations. Although a handful of new antibiotics have been approved in recent years, institutional wariness about potential overuse can restrict access to these drugs, posing a barrier to effective therapy for many high-risk patients.

For example, the efficacy of ceftolozane-tazobactam (Zerbaxa) against MDR strains like 

 prompted Marin General Hospital to add this agent to the formulary in 2016. Yet, despite its proven clinical efficacy and safety, many other US hospitals remain reluctant to add this agent, presumably because of its cost. Even where it is on the formulary, some physicians are hesitant to use ceftolozane-tazobactam, as part of a good-faith effort to reduce antibiotic over-prescribing. On the other hand, vague or loose usage guidelines at some hospitals may lead to antibiotic overuse, thereby undermining antimicrobial stewardship efforts.

Order Sets as an Antimicrobial Stewardship Tool

The potential for inappropriate use—including under- and over-use&mdash;of ceftolozane-tazobactam prompted Marin General Hospital to create and implement an electronic health record (EHR) order set for this agent. The creation of these types of order sets was a major goal of our institution’s antimicrobial stewardship team to ensure appropriate use of antibiotics in an expeditious and efficient manner. The backbone of these order sets is based on published clinical guidelines and US Food and Drug Administration (FDA)-approved recommendations. Rarely included are recommendations that are based on expert opinion. Without an order set, prescribing can be time-consuming for the physician and can delay initiation of treatment for patients facing life-threatening infections. Further, prescribing antimicrobials without the expert guidance of an order set can be haphazard and dangerous.

By requiring prescribers to use the order sets at Marin General Hospital, we aim to ensure the appropriate antibiotic is ordered for a specific indication, at the correct dose, and for the appropriate duration. The order sets also help to remind prescribers which antibiotic agents should not be used in a given scenario, as well as who is allowed to prescribe certain agents; for anyone not allowed to use a certain agent, the order set indicates whom to contact to arrange for its use.

Although the order sets require a few extra “clicks” on the EHR interface to complete an order, the extra effort is not onerous; indeed, the extra clicks are designed to help a physician confirm an appropriate choice of therapy, or discourage use of an inappropriate agent. Additionally, by prompting the physician to indicate the reason for the order, the order set provides more detailed information to the hospital pharmacist, who can contact the ordering physician in case of any questions about the order. The order set also reminds the physician to contact the microbiology lab if there are any questions about susceptibility testing.

Ceftolozane-tazobactam is a novel agent consisting of a novel cephalosporin antibacterial drug and a well-established beta-lactamase inhibitor, combined in a 2:1 ratio. Approved by the FDA in December 2014 for the treatment of complicated intra-abdominal infections (in combination with metronidazole) and complicated urinary tract infections including pyelonephritis, ceftolozane-tazobactam was the first gram-negative agent approved in this decade; its approval marked the half-way point for the Infectious Diseases Society of America “10 X ‘20 Initiative,” which aims to ensure the development of 10 new antimicrobial drugs by 2020.

 It is currently under investigation for the treatment of nosocomial bacterial pneumonia.

In terms of pharmacodynamics, ceftolozane-tazobactam has linear kinetics, and produces a greater than 3-log drop in bacterial load after 8 hours at 1 x minimal inhibitory concentration (MIC). It has a half-life of 2.6 hours, and is exclusively eliminated via the kidney; dose reduction is required in patients with renal diseases. Ceftolozane-tazobactam also provides excellent lung penetration and low protein binding. The pharmacodynamic parameter predicting bacteriological efficacy is the time above minimal inhibitory concentration (T > MIC) of the organism; Monte Carlo modeling predicted a simulated target attainment that 50% T > MIC of 8 mg/L achieved in 90% of subjects.

Starting in late 2016, the Marin General Hospital microbiology laboratory began testing all MDR 

strains for susceptibility to ceftolozane-tazobactam. Preliminary data are available from 139 clinical isolates of MDR 

. For ceftolozane-tazobactam, 95% of the isolates were susceptible. No isolates had full resistance; the remaining 5% of isolates had intermediate susceptibility. Susceptibilities of other antimicrobials tested included: colistin, 97.1%; and meropenem, 19.4%. This impressively high susceptibility profile in MDR isolates from our large community hospital is better than characteristics reported from recent clinical trials.

These same clinical trials also showed that ceftolozane-tazobactam had high activity against 

including many MDR strains, as well as against 

 isolates including most extended-spectrum beta-lactamase strains.

 strains with documented resistance to both ceftazidime and imipenem, ceftolozane-tazobactam was shown to have high activity; the only agent with consistently higher activity than ceftolozane-tazobactam was colistin. After 5 serial passages, investigators observed a 4-fold reduction in susceptibility for ceftolozane-tazobactam; comparatively, they observed 32-, 16- and 16-fold reductions for ceftazidime, imipenem and ciprofloxacin.

 Ceftolozane-tazobactam exhibited minimal cross-resistance with other antibiotics.

 Notably, efflux pumps—the main mechanisms of resistance against fluoroquinolones and carbapenems&mdash;had no effect on ceftolozane-tazobactam.

Since its implementation in December 2016, use of the ceftolozane-tazobactam order set has advanced antimicrobial stewardship efforts at Marin General Hospital. Due to low overall use of ceftolozane-tazobactam, before and after implementation of the order set, it is difficult to quantitate cost savings for the hospital. Other higher-volume antimicrobials with recently implemented order sets have demonstrated considerable reductions in utilization (eg, daptomycin decreased by 35% and ceftaroline decreased by 60%). These have resulted in constitutive cost savings for the hospital exceeding six figures depending on the time period assessed. Most importantly, the order set has helped establish a valuable niche for ceftolozane-tazobactam on the hospital formulary by exerting tight control on the use of this agent against MDR organisms, for which therapeutic options are limited. By ensuring appropriate use of ceftolozane-tazobactam (ie, in terms of indication, dose, and duration), the order set reduces the use of older, highly toxic antibiotic agents, benefits which improve patient outcomes.

The advent of antibiotic order sets is particularly timely in light of anticipated regulatory updates from the Centers for Medicare and Medicaid Services, which are expected to require institutions to specify the product name, indication, and duration of therapy for each antibiotic prescription order. Establishing order sets as routine practice will therefore facilitate regulatory compliance in a non-burdensome way.

The unfortunate steady increase in MDR bacterial clinical isolates in the United States will presumably lead to increased use of the ceftolozane-tazobactam order set, which is now 1 of 8 order sets in use at Marin General. Our department is currently developing order sets for 5 additional antimicrobial agents. We are optimistic that the use of these tools will yield similar benefits to those associated with the ceftolozane-tazobactam order set, and will advance antimicrobial stewardship overall.

Dr. Evens is a board certified physician in Internal Medicine and Infectious Diseases practicing in San Raphael, California. He is affiliated with several hospitals in the area, including Marin General Hospital, where he is 

 director of the Antimicrobial Stewardship Program, and Novato Community Hospital where he is 

 director of Infection Control. In 2018, he was featured in Top Doctor, Marin Magazine.

Disclosures: Dr. Evens is on the advisory board for Theravance and Gilead, and the speakers bureau for bioMe&#769;rieux, Astellas, Merck, and Theravance.

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Since its implementation in December 2016, use of a ceftolozane-tazobactam order set at Marin General Hospital has advanced antimicrobial stewardship efforts.

Alexander R. Evens, DO

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